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Transient Chemogenetic Inhibition of D1-MSNs in the Dorsal Striatum Enhances Methamphetamine Self-Administration

1
VA San Diego Healthcare System, San Diego, CA 92161, USA
2
Department of Anesthesiology, University of California San Diego, La Jolla, CA 92161, USA
*
Author to whom correspondence should be addressed.
Current address: University of New Mexico Health Sciences Center, Department of Cell Biology & Physiology, Albuquerque, NM 87131, USA.
Brain Sci. 2019, 9(11), 330; https://doi.org/10.3390/brainsci9110330
Received: 7 November 2019 / Accepted: 13 November 2019 / Published: 19 November 2019
(This article belongs to the Special Issue The Role of Dopamine in Neural Circuits)
The dorsal striatum is important for the development of drug addiction; however, the role of dopamine D1 receptor (D1R) expressing medium-sized spiny striatonigral (direct pathway) neurons (D1-MSNs) in regulating excessive methamphetamine intake remains elusive. Here we seek to determine if modulating D1-MSNs in the dorsal striatum alters methamphetamine self-administration in animals that have demonstrated escalation of self-administration. A viral vector-mediated approach was used to induce expression of the inhibitory (Gi coupled-hM4D) or stimulatory (Gs coupled-rM3D) designer receptors exclusively activated by designer drugs (DREADDs) engineered to specifically respond to the exogenous ligand clozapine-N-oxide (CNO) selectively in D1-MSNs in the dorsal striatum. CNO in animals expressing hM4D increased responding for methamphetamine compared to vehicle in a within subject treatment paradigm. CNO in animals that did not express DREADDs (DREADD naïve-CNO) or expressed rM3D did not alter responding for methamphetamine, demonstrating specificity for hM4D-CNO interaction in increasing self-administration. Postmortem tissue analysis reveals that hM4D-CNO animals had reduced Fos immunoreactivity in the dorsal striatum compared to rM3D-CNO animals and DREADD naïve-CNO animals. Cellular mechanisms in the dorsal striatum in hM4D-CNO animals reveal enhanced expression of D1R and Ca2+/calmodulin-dependent kinase II (CaMKII). Conversely, rM3D-CNO animals had enhanced activity of extracellular signal-regulated kinase (Erk1/2) and Akt in the dorsal striatum, supporting rM3D-CNO interaction in these animals compared with drug naïve controls, DREADD naïve-CNO and hM4D-CNO animals. Our studies indicate that transient inhibition of D1-MSNs-mediated strengthening of methamphetamine addiction-like behavior is associated with cellular adaptations that support dysfunctional dopamine signaling in the dorsal striatum. View Full-Text
Keywords: D1-MSNs; Fos; Erk1/2; Akt; CaMKII D1-MSNs; Fos; Erk1/2; Akt; CaMKII
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Oliver, R.J.; Purohit, D.C.; Kharidia, K.M.; Mandyam, C.D. Transient Chemogenetic Inhibition of D1-MSNs in the Dorsal Striatum Enhances Methamphetamine Self-Administration. Brain Sci. 2019, 9, 330.

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